There are two states of activity essential for normal glucose homeostasis—the absorptive or post-meal state and the basal or post-absorptive state. After a carbohydrate meal is ingested, the body's primary requirement is to maintain a normal plasma glucose level. To a large extent this glucose maintenance is accomplished by the secretion of insulin, which occurs in two main phases; an acute early phase and a secondary late phase. At the cellular level, insulin activates glucose transport and disposal pathways, with resulting storage as glycogen. Insulin secretion and glycemia suppresses hepatic glucose production (HGP), primarily by decreasing hepatic glycogenolysis. Gluconeogenesis, the other pathway by which the liver produces glucose, is also suppressed by physiologic concentrations of glucose but not by insulin.
The net effect of this homeostatic mechanism in normal individuals is that greater than 95% decrease in HGP is achieved by modest increases in plasma insulin and glucose concentrations. Insulin promotes cellular uptake of approximately 25% of the glucose load into insulin-dependent tissues-primarily muscles. The remaining 75% of the glucose load is taken up by insulin-independent tissues such as brain, splanchnic organs (liver and gut), erythrocytes, and kidneys at a rate proportional to the prevailing plasma glucose level. Adipose tissue is responsible for the disposal of less than 5% of a glucose load. Plasma glucose levels are maintained at a steady state by the liver through both glycogenolysis and gluconeogenesis. Thus, the rate of HGP is matched to glucose uptake by tissues, primarily through the action of insulin.
Diabetes mellitus, which currently afflicts at least 246 million people worldwide and expected to affect 380 million by 2025 is the fourth leading cause of global death by disease and is a group of diseases marked by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
One form of the disease is insulin-dependent diabetes mellitus (IDDM) or Type 1 diabetes and accounts for about 10% of diabetic population globally. IDDM is a result of autoimmune destruction of insulin-secreting β-cells in the pancreatic islets of Langerhans and is associated with insufficient insulin production causing metabolic changes, such as hyperglycemia, glycosuria and decreased hepatic glycogen levels. The most common form of diabetes is non-insulin dependent diabetes mellitus (NIDDM) or Type 2 diabetes, which accounts for the remaining 90% of individuals affected. Type 2 diabetes mellitus is a heterogeneous disorder characterized by two pathogenic defects, impaired insulin secretion and insulin resistance. Impaired insulin secretion leads initially to postprandial hyperglycemia, and as beta cell function declines further, fasting hyperglycemia ensues. Insulin resistance contributes further to and aggravates the fasting and postprandial hyperglycemia
It is well established in recent studies (Arch Inter Med. 2003; 163:1306-1316) that elevated glucose concentrations are an independent and clinically significant risk factor for cardiovascular disease in non-diabetic and diabetic individuals.
In a healthy individual, the basal blood glucose level is relatively constant from day to day because of an intrinsic feedback loop. Any tendency for the plasma glucose concentration to increase is counterbalanced by an increase in insulin secretion and a suppression of glucagon secretion, which regulate hepatic glucose production (gluconeogenesis and release from glycogen stores) and tissue glucose uptake to keep the plasma glucose concentration constant.
If an individual is stressed, gains weight or become insulin resistant for any other reason; blood glucose levels will increase, resulting in increased insulin secretion to compensate for the insulin resistance. Therefore, the glucose and insulin levels are modulated to minimize changes in these concentrations while relatively normal production and utilization of glucose are maintained.
Impaired glucose tolerance (IGT) characterized by glycemia between normal and overtly diabetic levels is a major risk factor for the development of NIDDM and is associated with an increased risk for macrovascular disease. Over 50% of potential NIDDM cases are undiagnosed and IGT is more prevalent amongst this population (National Diabetes Data Group and WHO criteria).
Insulin secretion in response to meals is multiphasic; a main biphasic mode in response of carbohydrate meals has been classified as first-phase or acute insulin response and defined as the initial burst of insulin released in the first 5-10 min after the pancreatic β cell is exposed to a rapid increase in glucose (or other secretagogues), and a second-phase insulin secretion which rises more gradually and is directly related to the degree and duration of the stimulus. Other modes of insulin release that have been identified include: 1) basal insulin secretion characterizing release in the post-absorptive state; 2) the cephalic phase of insulin secretion evoked by the sight, smell, and taste of food (before any nutrient is absorbed by the gut) and is mediated by pancreatic innervation; and finally, a third phase of insulin secretion that has only been described in vitro. During these stages, like many other hormones, insulin is secreted in a pulsatile fashion, resulting in oscillatory concentrations in peripheral blood.
Adequate glucose control is achieved in healthy individuals when the pancreatic β-cells generate an early response to a meal-like glucose exposure that rapidly elevates serum insulin both in the portal circulation and in the periphery. Conversely, in Type 2 diabetics, defective β-cells, which have an impaired first-phase insulin response, generate a sluggish response to the meal-like glucose exposure leading to post-meal hyperglycemia.
Postprandial hyperglycemia is now known to be a prominent and early defect in the etiology of Type 2 diabetes. It is also known and established in numerous studies that post-meal glucose excursions or postprandial hyperglycemia is associated with increased cardiovascular mortality in Type 2 diabetes (Diabetologia 39: 1577-1583; the DIS group 1996 Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up; Lancet 354:617-621DECODE Study Group, European Diabetes Epidemiology Group 1999 Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria., Diabetes study. Diabetes Care 22:920-A 1999 Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Fungata 924). In addition postprandial hyperglycemia has also been identified not only as a risk factor of cardiovascular disease among apparently healthy individuals but also directly linked to endothelia dysfunction, mortality in middle-aged non-diabetic males, (Circulation 2002:106:1211-1218 Ceriello A et al., Diabet Med. 2004, 21(2VnI-S. Ceriello A et al, and Diabetes Care 1998, 21(3):360-7. Balkau et al.), and as an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals (Arch Intern Med. (2004) 164:2147-2155. Levitan E B, et al., Atherosclerosis. (1999) 144(1):229-35, Hanefeld M et al.). The role of post-prandial glucose excursions, i.e. the incremental blood glucose response to exogenous glucose intake, in the development of microvascular complications in diabetes is also well established (JAMA 2002; 287:2414-23; The glycemic index-physiological mechanisms relating to obesity, diabetes and cardiovascular disease. Ludwig D S., and Arch Inter Med 2003; 163:1306-16; Clinical significance, pathogenesis, and management of postprandial hyperglycemia; Gerich J E.)
While conventional diabetes management guidelines recommends and advises monitoring of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) concentrations as a means of evaluating overall glycemic control, it is known that such FPG determinations does not provide information about the contribution of the postprandial rise in glucose levels to overall glycemic control. In fact HbA1c does not provide information relevant to the daily oscillations in blood glucose levels because it only represents the average glucose levels during the previous 2 to 3 months.
In addition, postprandial hyperglycemia occurs in approximately 40% of subjects who have achieved the recommended hemoglobin HbA1c targets (<7%) and in approximately 10% of diabetic subjects who have achieved normal fasting blood glucose levels (Diabetes Care 24:1734-1738 2001; Post challenge hyperglycemia in a national sample of U.S. adults with Type 2 diabetes; Erlinger T P, Brancati F L.). Post-meal glucose spikes are also estimated to account for 54% of glucose increments in diabetic subjects (Diabetes Care 25:737-741 2002 Morning hyperglycemic excursions: a constant failure in the metabolic control of non-insulin-using patients with Type 2 diabetes; Monnier L, Colette C, Rabasa-Lhoret R, Lapinski H, Caubel C, Avignon A, Boniface H) and are highly correlated with HbA1c (Diabetes Care 20:1822-1826 1997 Non-fasting plasma glucose is a better marker of diabetic control then fasting plasma glucose in Type 2 diabetes Avignon A, Radauceanu A, Monnier L)
In today's modern society with a breakfast, lunch, snack and dinner culture, a large part of the day is spent in the postprandial state which could lasts up to about 20 hours per day. The postprandial state has an estimated duration of 2-8 hours after each meal, depending on the nutrient content and the parameter measured (N Engl J Med 327:707-713 1992 Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. Dinneen S, Gerich J E, Rizza R, Diabetes 37:1020-10241988 Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM; Reaven G M, Hollenbeck C, Jeng C Y, Wu M S, Chen Y D). Most people are more often in a postprandial state rather than in a truly fasting state. Wide fluctuations in plasma glucose levels may occur throughout the day with high values 1 to 2 hours after a meal and low values before the next meal. Postprandial hyperglycemia is predominantly due to loss of insulin secretion in the first 30 min after eating (Diabetes Care 7:491-502 1984 Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus Ward W K, Beard J C, Halter J B, Pfeiffer M A, Porte D.) This β-cell defect results in inadequate suppression of hepatic glucose production and subsequent late hyperinsulinemia (Diabetes 48:99-105, 1999 Restoration of early rise in plasma insulin levels improves the glucose tolerance of Type 2 diabetic patients; Bruttomesso D, Pianta A, Mari A, Valerio A, Marescotti M, Avogaro A, Tiengo A, Del Prato S)
Thus, it is prudent and more useful to assess postprandial glucose levels in the monitoring of overall glycemic control. The postprandial glucose levels may more closely represent the metabolic processes involved in the pathogenesis of Type 2 diabetes—insulin resistance, increased hepatic glucose output, and impaired insulin secretion.
In a normal individual, the consumption of a meal induces a burst release of insulin, generating a rapid spike in serum insulin concentration that then decays relatively quickly. This early-phase insulin response is responsible for the suppression of endogenous glucose release from the liver. Homeostatic mechanisms then match subsequent insulin secretion (and serum insulin levels) to the glucose load. This is observed as a slow decay of modestly elevated serum insulin levels back to baseline in what is referred as second-phase kinetics.
Increasingly, evidence indicates that it is the early relatively rapid insulin response following glucose ingestion that plays the critical role in the maintenance of postprandial glucose homeostasis. An early surge in insulin concentration acts to limit initial glucose excursions, mainly through the inhibition of endogenous glucose production. Therefore, the induction of a rapid insulin response in a diabetic individual is expected to produce improved blood glucose homeostasis. In point of fact, Type 2 diabetics typically exhibit a delayed response to increases in blood glucose levels. While normal individuals usually begin to release insulin within 2-3 minutes following the consumption of food, Type 2 diabetics may not secrete endogenous insulin until blood glucose begins to rise significantly, with second-phase kinetics, which produces a slow rise and extended plateau in insulin concentration.
As a result of the defective first-phase “burst” insulin release, endogenous glucose production is not inhibited and continues well after meal consumption and the patient imminently experiences elevated blood glucose levels or hyperglycemia. As the disease progresses, the demands placed on the pancreas further degrades its ability to produce insulin and control of blood glucose levels gradually deteriorates. If unchecked, the disease can progress to the point that the deficit in insulin production approaches that typical of fully developed Type 1 diabetes. However, Type 1 diabetes can involve an early “honeymoon” stage, following an initial crisis, in which insulin is still produced but defects in release similar to early Type 2 diseases are exhibited.
While the relevance of insulin secretion abnormalities in the pathogenesis of Type 2 diabetes mellitus have been extensively debated, a clear consensus reached is that to fulfill its pivotal role in regulating glucose metabolism, insulin secretion must not only be quantitatively appropriate, but also possess qualitative, dynamic features that optimize insulin action on target tissues.
Furthermore, several clinical observations have confirmed that exaggerated post-breakfast hyperglycemia manifesting as high plasma glucose excursions over morning periods seems to be a permanent failure in non-insulin-using patients with Type 2 diabetes, regardless of their body weight, calorific and nutrient content of their meals, biological (HbA1c), therapeutic and pathophysiological (residual β-cell function) status. This circadian pattern of glucose response to meals is most likely due to impaired hepatic insulin sensitivity resulting in inadequate suppression of hepatic glucose output in the morning hours. In the same studies, it was demonstrated that hepatic glucose production peaks after an overnight fast and declines progressively to reach a nadir in the afternoon in Type 2 diabetes patients (Diabetes 45:1044-1050, 1996 Evidence for a circadian rhythm of insulin sensitivity in patients with NIDDM caused by cyclic changes in hepatic glucose production Boden G, Chen X, Urbain J L.). A similar mechanism is thought to cause fasting hyperglycemia due to the dawn phenomenon (N Engl J Med 310:746-750 1984 The “dawn phenomenon”—a common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus, Bolli G B, Gerich J E).
Thus, there is a great need for a safe, effective agent for decreasing postprandial glucose excursion in apparently healthy individuals, overweight persons, obese persons or persons with impaired glucose tolerance to prevent risk of cardiovascular disease.
Also, there is a great need for a safe, effective agent for reducing postprandial glucose excursion and postprandial hyperglycemia in Type 2 diabetic subjects to reduce risk of cardiovascular disease and other complications associated with postprandial glucose excursions.
Type 1 diabetic patients are currently treated with insulin, while the majority of Type 2 diabetic patients are treated either with agents that stimulate β-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. These agents are typically taken orally and thus collectively referred to as oral hypoglycemic agents. The most common insulin sensitizing oral hypoglycemic agents are the glitazones (e.g. pioglitazone and rosiglizatone) and the biguanides (e.g. buformin and metformin).
The currently available oral hypoglycemic agents and other insulinotropic agents while effective in lowering glucose levels in blood are not completely effective in overcoming the hepatic insulin resistance that not only magnifies post-breakfast glycemic excursions but also typically contributes to post-lunch and post-supper glycemic excursions. Among the safe, effective oral hypoglycemic agents, the guanidine derivative metformin still remains the most commonly prescribed oral anti-diabetic drug indicated for use in the management of Type 2 diabetes.
Metformin is a hepato-selective insulin sensitizer, which successfully lowers fasting blood glucose and % HbA1C and does not cause hypoglycemia or hyperinsulinemia. Although it has been in clinical use for over three decades, the known therapeutic profile has been largely based on treatment from conventional immediate release formulations that require administration two or three times daily and more recently extended release formulations that allow for a once-daily administration. The effectiveness of these formulations has been based principally on lowering glycated hemoglobin (HbA1C) and fasting blood glucose. Since HbA1C is a posttranslational modification formed by slow non-enzymatic attachment (glycation) of glucose to adult hemoglobin (HbA0), the degree of hemoglobin A1C can be used as a measure of average glycemia over the preceding 2 to 3 months and has been adopted in clinical practice as the gold standard for assessment of long-term glycemic control.
U.S. Pat. No. 3,174,901 discloses the biguanide antihypertensive agent metformin. The immediate release formulation in the form of the hydrochloride salt is currently marketed in the U.S. under the trade name Glucophage® tablets by Bristol-Myers Squibb Co. Each Glucophage® tablet contains 500, 850 or 1000 mg of metformin hydrochloride. There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with Glucophage®. The dosage of Glucophage® is individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended dose of 2550 mg per day. However, being a short acting drug, metformin requires twice-daily (b.i.d.) or three-times-a-day (t.i.d.) dosing. Adverse events associated with metformin use are often gastrointestinal in nature (e.g., anorexia, nausea, vomiting and occasionally diarrhea, etc.). These adverse events may be partially avoided by reducing the initial and/or maintenance dose or using an extended release dosage form.
U.S. Pat. No. 6,660,300 discloses compositions and techniques used to provide controlled and extended-release pharmaceutical dosage forms of metformin in order to provide a once-daily therapy and reduce the incidence of adverse events associated with the immediate release counterparts. It is reported in the 50th Edition of the Physicians' Desk Reference, copyright 1996, p. 753, that “food decreases the extent and slightly delays the absorption of metformin delivered by the Glucophage® dosage form. This decrease is shown by approximately a 40% lower peak concentration, a 25% lower bioavailability and a 35-minute prolongation of time to peak plasma concentration following administration of a single Glucophage® tablet containing 850 mg of metformin hydrochloride with food compared to the similar tablet administered under fasting conditions”.
Methods of producing extended release metformin dosage forms, herein referenced by U.S. Pat. Nos. 6,660,300; 6,099,862; 6,340,475 and 6,488,962 have taught that it is possible to provide an extension of metformin release by prolonging the residence time in the upper gastro-intestinal tract. These prior art dosage forms have in one way or another provided for prolonged gastric residence as a plausible mechanism of extending release of metformin by essentially combining a mechanism that resists normal gastric transit times for solid materials and the physiological effect, on absorption, of prolonged gastric residence in the fed state and more preferably in the high-fat fed state.
Studies by Vidon et al (Diabetes Res Clin Pract. 1988 Feb. 19; 4 (3):223-9 3359923) strongly suggest that the delivery process was the rate-limiting factor for metformin absorption from the gastro-intestinal tract and that there is permeability limited absorption of metformin. The orally administered drug will transit down the small intestine following dissolution from an ingested dosage form and, if absorption rate is slow, it is possible that the drug can reach regions of poor permeability before absorption from a given dose is complete.
It is known that extending the release of metformin oral formulations invariably compromises and reduces the bioavailability of the drug. This result is probably because the dosage form carries a significant proportion of the drug content remaining to be released to regions of the gastro-intestinal tract with very poor permeability to the drug. To reduce dosing frequency, the rate of release from the dosage form must be such as to extend effective plasma levels, but the potential for effective delivery at this rate is compromised by the combined effect of significant reduction in permeability to the drug in passing from the proximal small intestine to the colon and the limited residence time of the dosage form in the regions of the gastro intestinal tract where the drug is intrinsically well absorbed.
While several prior art extended release metformin dosage forms have overcome the challenge of prolonging the release of metformin by extending the time to maximum plasma concentrations in the order of 6-8 hours, they are only achievable under high-fat fed conditions, contrary to recommended diets for patients with diabetes, and with a significant reduction of maximum plasma concentration. Furthermore these extended release formulations exhibit very significant food effect pharmacokinetics which adds to the intra subject variability during multiple dosing regimens.
In the case of one prior art extended release metformin formulation Glucophage® XR described in U.S. Pat. No. 6,660,300, when taken with a meal, the Cmax is achieved with a median time of 7.0 hours and the peak plasma concentration is 20% lower compared to the same dose of the immediate release Glucophage®, however the extent of absorption (measured by AUC) is similar to Glucophage®.
In the case of another prior art extended release metformin formulation Fortamet® described in U.S. Pat. No. 6,099,862, when taken with a meal, the Cmax is achieved with a median of 6.1 hours and the Cmax is 30% higher than that achieved in the fasting state. Furthermore, the extent of absorption (as measured by AUC) is 60% higher in the fed state in comparison to the same dose given in the fasted state.
In the case of yet another prior art extended release metformin formulation Glumetza® described in U.S. Pat. Nos. 6,340,475 and 6,488,962, when taken with a meal, the Cmax is achieved with a median of 7 hours, and the peak plasma concentration is 18% lower when compared to the same dose of the immediate release metformin, however the extent of absorption (as measured by AUC) is similar to immediate release metformin. Furthermore, there is a difference of 35% in the extent of absorption (as measured by AUC) when Glumetza® is taken with a low fat and a high fat meal. The AUC is higher with the high-fat meal.
It is clearly evident in these aforementioned prior art teachings of extended release metformin formulations that none can achieve comparable peak plasma concentration as compared to the same dose of the immediate release formulation in both fed and fasted states. The Cmax is significantly reduced most compromised in the fed state which ironically is the preferred mode of administration for both prior art immediate and extended release formulations. It is also evident that none can achieve a comparable extent of drug absorption as compared to the same dose of the immediate release formulation when taken in the fasted state or before meals. The extended release formulations, by virtue of the preferred mode of administration necessary for dosage form functionality exhibits a grossly reduced extent of drug absorption in the fasted state when compared to the same dose of the immediate release counterpart in the fasted state or of the same extended release formulation in the fed state.
While prior art teachings of extended release metformin have proffered obvious patient compliance improvements due to reduced frequency of administration, and reduced gastrointestinal adverse effects due to reduced rate of drug release from the dosage form in the gastrointestinal tract, it has not been shown that an improvement or at least a comparable clinical efficacy can be obtained when compared with the same doses of immediate release formulation taken in the fasted state or fed states. For example a 24 week, double blind, randomized study of the prior art extended release metformin formulation Glucophage® XR, taken 1000 mg once daily with evening meal and the immediate release metformin 500 mg Glucophage®, taken twice daily (with breakfast and evening meal), was conducted in patients with Type 2 diabetes. In this study, patients qualified for the study had glycosylated hemoglobin (HbA1c) of ≦8.5% and fasting plasma glucose (FPG) levels of ≦200 mg/dL. After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the Glucophage® XR 1000 mg group the increase from baseline of 0.23% was statistically significant. The Glucophage® 1000 mg (500 mg b.i.d.) had an increase of 0.14%. Increased HbA1c levels after treatment intervention is indicative of impaired or poor efficacy.
It is evident that prior art teachings of metformin methods and compositions, immediate release and extended release are a) are not suited for administration before meals, b) not directed towards or suited for reducing postprandial glucose excursions, c) not able to overcome the undesirable food effect pharmacokinetics of drug. Furthermore, according to the drug monograph for Glucophage®, “the therapeutic goal of metformin according to the monographs is to achieve a decrease in both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Glucophage® or Glucophage® XR, either when used as monotherapy or in combination with sulfonylurea or insulin”.